Research focuses on molecular messenger systems characterized in the Snyder laboratory which are substrates for actions of drugs of abuse. One involves a signaling cascade linking nitric oxide (NO), glyceraldehyde-3-phosphate dehydrogenase (GAPDH), the ubiquitin E3-ligase Siah-1 and nuclear targets. A second deals with inositol hexakisphosphate kinase-2 (IPK6K2) in cell death and neurotoxicity, while a third addresses inositol polyphosphate multikinase (IPMK) and neural function. The NO-GAPDH-Siahl pathway was discovered as a cell death signaling system acting via nuclear p53. Recent work reveals a physiologic role wherein nitrosylated GAPDH, responding to neuronal growth factors, via Siah-1, degrades the histone methylating enzyme SUV39H1 leading to histone acetylation, gene transcription and dendritic outgrowth. Cocaine, in behavioral stimulant doses, activates this pathway. We will elucidate this pathway. IP6K2, a mediator of apoptosis, acts via p53. We are assessing how it distinguishes cell arrest/cell death via influences upon DNA protein kinase to activate p53. Its role in cocaine and MPTP actions is being investigated. IPMK is an inositol phosphate kinase and a PI3-kinase. We recently discovered that it is physiologically nitrosylated and acetylated, then binds to CBP and CREB, apparently activating CREB genetic programs. Cocaine administration activates IPMK nitrosylation/acetylation. We will explore its neural functions using newly generated IPMK knockout mice. We recentiy discovered that IPMK binds the small G-protein Rheb, known to activate mTOR. We previously showed that IPMK binds and stabilizes mTOR. We will investigate whether IPMK/Rheb coordinately regulate mTOR signaling in the brain in response to abusable drugs. RELEVANCE (See instructions): Our research elucidates how the NO-GAPDH-Siah signaling cascade mediates neural messages including actions of cocaine. The work on IP6K2 and IPMK is similariy relevant, especially the novel potential role of nitrosylated/acetylated IPMK as a regulator of genetic programs impacted by cocaine.